IN SILICO INVESTIGATION OF XANTHONE DERIVATIVE POTENCY IN INHIBITING CARBONIC ANHYDRASE II (CA II) USING MOLECULAR DOCKING AND MOLECULAR DYNAMICS (MD) SIMULATION Original Article REGINA KATELIA 1 , MUHAMMAD MIFTAH JAUHAR 2 , PUTRI HAWA SYAIFIE 2 , DWI WAHYU NUGROHO 2 , DONNY RAMADHAN 3 , ADZANI GAISANI ARDA 2 , ETIK MARDLIYATI 4 , ISA ANSHORI 1* 1 Biomedical Engineering Department, School of Electrical Engineering and Informatics, Bandung Institute of Technology, Bandung, Indonesia, 2 Nano Center Indonesia, Jl. PUSPIPTEK, South Tangerang, Banten, 15314, Indonesia, 3 Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Cibinong, Bogor, Jawa Barat, 16911, Indonesia, 4 Research Center for Vaccine and Drug, National Research and Innovation Agency (BRIN), Cibinong, Bogor, Jawa Barat, 16911, Indonesia Email: isaa@staff.stei.itb.ac.id Received: 31 May 2022, Revised and Accepted: 16 Jul 2022 ABSTRACT Objective: Hypertension is the leading contributor to all-cause death and disability worldwide. One of the most well-known first-line antihypertensive drugs is chlorthalidone which treats hypertension through carbonic anhydrase (CA) II inhibition. However, due to the high number of cases of hypertension, a more potent medication is still needed. Xanthone is a potential candidate for the compound group for its potency in inhibiting CA II. Therefore, this research aims to evaluate around 500 xanthones’ potency as a better oral antihypertensive drug than chlorthalidone. Methods: 507 xanthones were analyzed for their potency using in silico method. Xanthone’s structures were retrieved from the PubChem website or built using Avogadro software, while the CA II receptor was retrieved from The RCSB website. Then molecular docking, ADME evaluation, and toxicity test were evaluated from selected ligands. Finally, a molecular dynamics simulation was conducted to evaluate the stability of the potential ligand as the inhibitor of CA II protein. Results: This research found that globulixanthone c is considered to be a better CA II inhibitor compared to chlorthalidone. It is due to its lower binding affinity compared to chlorthalidone and its stable binding to CA II’s important inhibition sites with low fluctuation. It also has the potential to be consumed orally because it fulfills all of Lipinski's rule of five standards and its toxicity is on the moderate level. Conclusion: Globulixanthone c, a type of prenylated xanthones group, showed the best potential activity as the inhibitor of CA II protein to treat hypertension among other xanthones. Keywords: Carbonic anhydrase (CA) II, Hypertension, Xanthone, Molecular docking, Molecular dynamics © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2022v14i5.45388. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Systemic arterial hypertension (or hypertension) is a condition characterized by persistently high blood pressure (BP) in the systemic arteries. BP is often stated as the ratio of the systolic BP (that is, the pressure that blood exerts on the arterial walls when the heart contracts) and the diastolic BP (the pressure when the heart relaxes) [1]. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 7 categorizes the disease as a condition when one’s systolic/diastolic pressure exceeds 140/90 mmHg [2]. Hypertension becomes the most common risk factor for cardiovascular disease (CVD), chronic kidney disease (CKD), and cognitive impairment. It is the single leading contributor to all-cause death and disability worldwide [1]. According to WHO (2021), 1.13 of 7.8 billion of the world’s population are diagnosed with hypertension, and the disease itself is estimated to cause 7.5 million deaths (which is 12.8% of total deaths) worldwide [3, 4]. The high level of hypertension cases and deaths caused by it make hypertension treatment become crucial to lower the world’s morbidity level and increase global life expectancy. Some researchers conducted research on targeting certain proteins involved in hypertension using natural products and a standard drug to elaborate the activity and potential pathway inhibition. Demir (2019) revealed the potential inhibitor of some antihypertension drugs to PON1 protein that links with another disease [5]. In addition, Demir (2020) also showed the potential of quinones as an antihypertensive agent [6]. One of the most common first-line antihypertensive medications is thiazide diuretics with chlorthalidone as the most commonly used drug in the group [7]. In lowering blood pressure, chlorthalidone’s important mechanism is carbonic anhydrase (CA) inhibition [8]. Carbonic anhydrase (EC 4.2.1.1) is a group of metalloenzymes that catalyzes the hydration of CO2 and H2O into bicarbonate and hydrogen ions [9]. This enzyme plays a role in various physiological processes in various organisms, including humans, therefore, the abnormal level or activity of this enzyme can trigger diseases [9, 10]. Agree with that, inhibition of this enzyme becomes crucial to treat some diseases and to examine the new potential drug for clinical applications [11]. In the human body, there are 13 catalytically active CA isozymes that spread in various concentrations and locations [8]. These are classified according to crucial properties such as inhibitor sensitivity, catalytic activity, and subcellular location [12]. Amongst these isozymes, isozymes I, II, III, IV, V, IX, XII, and XIV have relevance in cardiovascular regulation. From them, CA II is counted as a very potent drug target to lower blood pressure because of its high activity (105-6/sec) and its various locations–red cells, kidney, lung, heart, brain, vascular smooth muscle, and endothelium. However, some research revealed the side effects of thiazide diuretics, especially from chlorthalidone treatment, such as hypokalemia, hyperglycemia, myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease [13, 14]. Therefore, the necessity of looking for a new hypertension treatment is still required. Xanthones as a group of secondary metabolites are normally found in a restricted assembly of higher plants (mostly family Clusiaceae and Gentianaceae), fungi, and lichens. This compound group has a symmetrical parent compound–9H-xanthen-9-one and was classified into six groups–simple xanthones, glycosylated xanthones, prenylated xanthones, xanthonolignoids, bis-xanthones, and miscellaneous International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 14, Issue 5, 2022